Drug likeliness, pharmacokinetics profiling and efficacy of Polyscias fulva bioactive compounds in the management of uterine fibroids; An integrative in silico and in vivo approach

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling Pub Date : 2025-02-19 DOI:10.1016/j.jmgm.2025.108984

Kenedy Kiyimba , Lincoln Munyendo , Samuel Baker Obakiro , Yahaya Gavamukulya , Ayaz Ahmed , Mohammed Iqbal Choudhary , Muhammad Shafiq , Zaheer Ul-Haq , Eric Guantai

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引用次数: 0

Abstract

Polyscias fulva is traditionally used in Uganda for the management of Uterine fibroids (UF). However, there is paucity of data regarding its efficacy, biological targets and potential mechanisms of action hence prompting scientific validation process through insilico and invivo approaches. In this study, we utilized network pharmacology, molecular docking, molecular dynamic simulations and invivo assays to investigate the drug likeliness, pharmacokinetics and efficacy of Polyscias fulva against Uterine fibroids.

Four Polyscias fulva bioactive compounds; pinoresinol, lichexanthone, methyl atarate, β-sitosterol exhibited drug likeness properties with moderate safety profiles. Forty-eight (48) uterine fibroid targets were identified as potential targets for the eleven Polyscias fulva compounds. Protein-protein interaction (PPI) analysis revealed four key targets (HIF1A, ESR1, EGFR, and CASP3). The KEGG pathway and GO enrichment analyses revealed that these key targets play significant roles in regulating the positive regulation of cyclin-dependent protein serine/threonine kinase activity, positive regulation of nitric-oxide synthase activity and positive regulation of transcription, DNA-templated. β-sitosterol demonstrated the strongest binding affinity with the four targets, showing particularly strong affinities for EGFR (−9.75 kcal/mol) and HIF1A (−9.21 kcal/mol). Molecular dynamics (MD) simulations revealed high stability in these protein-ligand complexes, with CASP3 displaying the lowest deviation and most consistent RMSD (0.14 nm) of the protein, followed by EGFR (0.25), HIF1A (0.29), and ESR1 (0.79). In-vivo evaluation on female Wistar rats with Polyscias fulva ethanolic extract showed an ameliorative effect of the extracts against monosodium glutamate-induced (MSG) UF. Treated animals exhibited a decrease in serum proteins, cholesterol, estrogen, and progesterone levels (P < 0.05) and the extract preserved uterine tissue histoachitecture as compared to controls. In conclusion, Polyscias fulva demonstrates potential ameliorative activity against UF with promising pharmacokinetic properties and safety profiles.

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茯苓多糖生物活性化合物治疗子宫肌瘤的药物可能性、药代动力学分析及疗效观察一个集成的在硅和在体内的方法

富尔瓦多糖传统上在乌干达用于子宫肌瘤（UF）的管理。然而，缺乏关于其功效、生物学靶点和潜在作用机制的数据，因此需要通过体内和体外方法进行科学验证。本研究采用网络药理学、分子对接、分子动力学模拟和体内实验等方法，研究茯苓多糖对子宫肌瘤的药效、药代动力学和疗效。四种茯苓多糖生物活性化合物；松脂醇、lichexanthone、甲酯、β-谷甾醇表现出与药物相似的特性，具有中等的安全性。鉴定了48个子宫肌瘤靶点为11种茯苓多糖化合物的潜在靶点。蛋白-蛋白相互作用（PPI）分析揭示了四个关键靶点（HIF1A、ESR1、EGFR和CASP3）。KEGG通路和GO富集分析表明，这些关键靶点在调节细胞周期蛋白依赖性蛋白丝氨酸/苏氨酸激酶活性、一氧化氮合酶活性和转录、dna模板化的正调控中发挥重要作用。β-谷甾醇与这四个靶点的结合亲和力最强，对EGFR （- 9.75 kcal/mol）和HIF1A （- 9.21 kcal/mol）的亲和力最强。分子动力学（MD）模拟显示，这些蛋白-配体复合物具有很高的稳定性，其中CASP3的偏差最小，RMSD最一致（0.14 nm），其次是EGFR（0.25）、HIF1A（0.29）和ESR1（0.79）。茯苓多糖乙醇提取物对雌性Wistar大鼠的体内评价表明，茯苓多糖乙醇提取物对味精诱导的UF有改善作用。治疗后的动物血清蛋白、胆固醇、雌激素和黄体酮水平下降(P <；0.05)，与对照组相比，提取物保存了子宫组织的组织结构。综上所述，茯苓多糖对UF具有潜在的改善作用，具有良好的药动学特性和安全性。

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来源期刊

Journal of molecular graphics & modelling 生物-计算机：跨学科应用

CiteScore

5.50

自引率

6.90%

发文量

216

审稿时长

35 days

期刊介绍： The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design. As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.